2023-2024 Creams and Ointments - Tagged PDF

Pharmaceutical Science and Formulation I Creams, Ointments and Gels Dr. Jihong Han Room: HNB 0.54b E-mail: [email protected]  Outline Part 1. General aspects of creams Part 2. Structure of creams and gel network theory Part 3 Attributes and manufacture of...

Pharmaceutical Science and Formulation I Creams, Ointments and Gels Dr. Jihong Han Room: HNB 0.54b E-mail: [email protected]  Outline Part 1. General aspects of creams Part 2. Structure of creams and gel network theory Part 3 Attributes and manufacture of creams Part 4. Ointments and gels Part 1. General aspects of creams  Introduction Historically, topical semisolids were developed with emphasis on cosmetic considerations, rather than scientific principles – Creams – Ointments – Gels – Pastes These semisolids often display non-Newtonian characteristics, e.g. plastic, pseudoplastic, or thixotropic type flow Factors that traditionally distinguished an ointment from a cream were not well defined – Sometimes the terms ‘creams’ and ‘ointments’ are used interchangeably (but scientifically should not!) – Hydrous Ointment (BP) is often referred to as Oily Cream  Creams - general Creams are semi-solid preparations intended for external use – Aqueous creams: o/w emulsions – Oily creams: w/o emulsions – The aqueous phase of a cream is often structured by the addition of structuring materials, e.g. clay particles, polymers forming lamellar gel network phases as a result of the interaction between some emulsifiers and water Essentially miscible with the skin secretion For protective, therapeutic purpose Some other water-miscible bases that have a complex matrix- like structure are also called ‘creams’ as they have cream-like appearance and consistency. In other words, some are called ‘creams’ simply because they feel (or look) like a cream (not scientific!)  Hydrophilic creams Aqueous phase as the continuous phase – O/W emulsions – Non-greasy texture – Water washable – Non-occlusive – The continuous phase evaporates (drug concentration in adhering film increases) – Topical administration of drugs What about lipophilic creams?  Creams - emulsifiers The most commonly used emulsifiers – Lipophilic amphiphiles, such as fatty alcohols, fatty acids (in large quantities) – Water soluble surfactants (ionic or non-ionic) You need to keep the HLB concept in mind, and understand how the HLB can be used to indicate how hydrophilic or how lipophilic a surfactant is You may also need to check the chemical structure of the surfactant if necessary Refer to lectures on Emulsions for more information about emulsifiers Fatty amphiphile Surfactant Which is more hydrophilic? Cetyl alcohol Sodium stearate A. Stearyl alcohol Stearyl alcohol Triethanolamine stearate B. Stearyl acid C. Sodium stearate Cetosteryl alcohol Sodium lauryl sulphate Steric acid Cetrimide Glyceryl monosterate Cetomacrogol 1000  Creams - emulsifiers Ready made mixtures, e.g. – Emulsifying Ointment (BP) Emulsifying Wax 300 g White Soft Paraffin 500 g Liquid Paraffin 200 g – Emulsifying Wax (BP) Cetostearyl Alcohol 90 g Sodium Lauryl Sulphate 10 g Purified Water 4 ml – Aqueous cream (BP) – an example of creams Emulsifying Ointment 300 g Phenoxyethanol 10 g Purified Water to produce 1000 g Part 2. Structure of creams and gel network theory  Stability of creams - conventional theories about emulsions Refer to emulsions lectures – Droplet size – Creaming – Coalescence – Etc More relevant to creams when they are at high temperatures (hence more liquid than at low temperatures) – Interfacial energy/tension – Interfacial film of emulsifiers – Charge repulsion – Steric stabilisation Stability and gel network structure The external phase tends to form certain structure – the droplets will be immobilised which will stabilise the creams The structure of external phase can be due to – Gel forming polymers – Lamellar gel network theory Excess amount of lipid amphiphiles are used in creams, more than that can be adsorbed at the o/w interface -Crystalline gel-network phase formed upon contact with water Self bodying effect: more fluid at low concentrations, more rigid (semisolid) at high concentrations (more details later) Interaction between the emulsifiers in water is the key  Interaction of emulsifiers in water Long chain alcohols exist in three different polymorphs – -form: high temperature, come out first when cooled. Only stable over a narrow temperature range – -form and -form: at lower temperatures, these two forms can coexist (including room temperature) Transition temperature of the lipid amphiphiles (long chain alcohol) is reduced when in the form of mixtures. So at room temperature: – Pure cetyl or stearyl alcohol may exist as - and -crystalline polymorphs – Cetostearyl alcohol (a mixture of cetyl and stearyl alcohol) may exist as - crystalline forms Formation of -crystalline is the prerequisite to form liquid crystalline and swollen crystalline phases  Lamellar gel network theory + Surfactants Water Tc -Hydrate -Crystalline gel Liquid crystalline Fatty amphiphilic molecules Surfactant molecules -Crystalline shows limited swelling in excess of water After a small amount of surfactants is added, it swells significantly to form a viscoelestic -Crystalline gel phase After heated to Tc, it transforms to a less swollen liquid crystalline state The crystalline gel net work traps and immobilises the oil droplets, hence stabilises the cream  Interaction of emulsifiers in water -crystalline forms waxy crystalline hydrates with limited swelling in presence of water In the presence of small amount of surfactants (alcohol to surfactant molar ratio 10-30 : 1), it forms -crystalline gel phase – Viscoelastic – Associated with increased swelling The -crystalline gel phase changes to a less swollen liquid crystalline form upon heating to Tc (gel liquid transition temperature)  Interaction of emulsifiers in water Upon cooling below Tc, it reverts back to the swollen gel phase – Tc is usually between 40-50°C for cetostearyl alcohol and other commonly used amphiphiles in creams – During manufacturing process (high temperatures): liquid crystalline state. The cream is less viscous – After manufacture, upon cooling, it hardens (more viscous), sometimes the transition temperature is called ‘the setting temperature’  Microstructure of creams Figure 27.4. Aulton 4th edition, p452 When water is freely movable, the viscosity is low. When water is trapped in gel structure, the viscosity is increased.  Microstructure of creams The dispersed oil droplets stabilised by – Monolayer emulsifier film – Charge The viscoelastic continuous phase – -Crystalline gel phase: bilayers of fatty alcohol and surfactant separated by interlamellar fixed water (significant swelling) – -Crystalline hydrate (limited swelling) – Bulk continuous free water  Specific emulsifier mixtures Fatty alcohol with ionic emulsifiers – Extensive swelling: water layer is 10 times thicker than the carbon layer – Electrically charged – DLVO theory applies to adjacent bilayers (Refer to emulsions and colloids lectures) – Addition of electrolytes will Compress the electric diffuse double layer, and reduce the repulsion between adjacent bilayers (review diffuse double layer and DLVO theory) Reduce the volume of the lamellar gel-network phase Reduce viscosity Specific emulsifier mixtures Fatty alcohol with ionic emulsifiers  Specific emulsifier mixtures Fatty alcohol with polyoxyethylene (PEO) surfactants – Swelling due to the hydration of the PEO chain – Steric stabilisation: PEO chain extends into the water layer – At high temperature shortly after preparation: PEO chain less well hydrated, no gel phase formed, relatively more fluidic – During storage at low temperature: PEO better hydrated, more swelling due to the formation of gel phase, more viscous PEO is more hydrated at low temperature. PEO containing surfactants: more soluble at low temperature. Specific emulsifier mixtures Fatty alcohol with polyoxyethylene (PEO) surfactants  Specific emulsifier mixtures Fatty acid mixed emulsifiers – Fatty acids Polymorphisms Vanishing cream: appears to be vanishing when being applied, leaving a ‘non-greasy’ residue on the skin – Stearate cream: stearic acids partially (10-40%) neutralised by alkali, e.g. Triethanolamine: forms swollen lamellar structure NaOH, or KOH – Does not appear to form swollen lamellar structure – forms disordered interlinking bilayers of mixed emulsifiers (twisted ribbon), entrapping large amount of water Part 3 Attributes and manufacture of creams Structure factors and attributes of creams Perceivable attributes of creams: – Overall consistency – Cosmetic appearance – Rheological properties – Rheological stability over a period of time (thinning or thickening) Structure factors affecting the above attributes – The mechanisms and kinetics involved in the formation of the various phases – The thickness of the interlamellar water layers – The proportion of added water that is between the lamellae – The relative proportions of the various phases – The stability of the various phases over different temperatures and batch variation of the components  Liquid emulsions vs creams Oil droplets Viscoelastic multicomponent gel Aqueous phase phase (Pattern does not represent actual structure) Liquid emulsions Creams (o/w) Oil droplets free moving Oil droplets are effectively -May coalesce, immobilised in the gel phase - May flocculate - No creaming - May move to top forming a cream - No coalescence layer - No flocculation Structure of gel phase is important  Self-bodying action The rheological properties of creams are strongly dependent on the concentration of the mixture of emulsifiers due to the swelling properties of the lamellar gel-network phase At low concentrations of emulsifiers – Structured liquid, and – High proportion of free water – More fluidic At high concentrations of emulsifiers – Increased proportion of swollen lamellar gel-network phase – Reduced proportion of free water – More viscous  Manufacture of creams More complex than liquid emulsions due to the formation of structures in the continuous phase The microstructures are sensitive to the dynamic manufacture process – Scaling up must be carefully controlled – Each type of equipment introduces energy into the system in a different way – Creams prepared from large production equipment could be very different from small laboratory equipment – Other variations, e.g. heating and cooling cycles  Terbinafine 1 % Cream Contains: 10 mg terbinafine hydrochloride (equivalent to 8.89 mg of terbinafine) per g of cream Application: For cutaneous use Excipients with known effect: – 10 mg benzyl alcohol per gram of cream – 40 mg cetostearyl alcohol per gram of cream – 40 mg cetyl alcohol per gram of cream List of excipients – Cetyl palmitate – Cetyl alcohol – Cetostearyl alcohol – Sorbitan monostearate – Polysorbate 60 – Isopropyl myristate (moisturiser, emollient) – Sodium hydroxide – Benzyl alcohol – Purified water Manufacturer: Mylan (now part of Viatris) Why there are so many excipients?  Canesten Cream Contains: Clotrimazole 1% w/w Indications – All dermatomycoses due to moulds and other fungi (e.g. Trichophyton species). – All dermatomycoses due to yeasts (Candida species). – Skin diseases showing secondary infection with these fungi. – Candidal nappy rash, vulvitis and balanitis. Application: applied thinly on hands or feet Excipients with known effect: – Cetostearyl alcohol 100mg per gram of cream – Benzyl alcohol 20mg per gram of cream List of excipients – Cetostearyl alcohol – Octyldodecanol – Cetyl palmitate – Polysorbate 60 – Sorbitan stearate – Benzyl alcohol – Purified water Manufacturer: Bayer plc  Canesten Antifungal Cream Contains: Clotrimazole 1% w/w Indications – All dermatomycoses due to moulds and other fungi, (e.g. Trichophyton species). – All dermatomycoses due to yeasts (Candida species). – Skin diseases showing secondary infection with these fungi. – Candidal nappy rash, vulvitis and balanitis. Application: applied thinly on hands or feet Excipients with known effect: – Cetostearyl alcohol 100mg per gram of cream – Benzyl alcohol 20mg per gram of cream List of excipients – Cetostearyl alcohol – Octyldodecanol – Cetyl palmitate – Polysorbate 60 – Sorbitan stearate – Benzyl alcohol – Purified water Manufacturer: Bayer plc [Discontinued] Part 4. Ointments and gels  Ointments An ointment consists of a single-phase base in which solids or liquids may be dispersed Highly viscous and moisture occlusive - emollient, protective and therapeutic effects Medicaments can be dissolved or dispersed in ointments Hydrophobic ointments – Can absorb only a small amount of water – Occlusive effect – Typical bases: heavy liquid and light liquid paraffins, vegetable oils, animal fats, synthetic glycerides, waxes and liquid polyalkylsiloxanes  Ointments Water-emulsifying ointments – Can absorb larger amounts of water – Results in water-in-oil or oil-in-water emulsions Hydrophilic ointments – Bases are miscible with water, e.g. polyethylene glycols (Macrogols) – May contain appropriate amounts of water – Less emollient  Preparation of ointments Melt the base at high temperature (above melting point) Mix: excipients, drugs Cool – avoid separation of different materials May need special equipment, e.g. rollers, to maintain smoothness Aciclovir Agepha 30 mg/g eye ointment Contains: 30 mg aciclovir per gram of cream Indication: for the treatment of herpes simplex keratitis Administration: Ocular use List of excipients – White soft paraffin  Gels Semi-solid systems (usually) Colloidal particles may link together to form a 3- D network formation Water molecules held within 3-D network Some gels (e.g. hydrogels) can hold ~90% water Gels usually thin after application of a small shear stress, and are amenable to topical application  Types of gel Gelation of lyophilic colloids (polymers) – Type I Covalent bonds between the macromolecules Irreversible system The crosslinking system created by the polymers is not dissolvable Polymeric implants Sustained release of drugs e.g. 2-hydroxyethylmethacrylate (HEMA) cross linked with ethylene glycol dimethacrylate – Type II Hydrogen bonds or van der Waals forces Heat-reversible (heating or cooling) e.g. polyvinyl alcohol Which type of gels will show a change in viscosity when a shear stress is applied? What type of flow do hydrophilic gels tend to demonstrate?  Types of gel Gelation of lyophobic colloids (sols) – Particles of lyophobic colloids may link together to form gels, e.g. Bentonite Aluminium magnesium silicate – Van der Waals forces – Electrostatic attraction between the particles – When a shear stress is applied (e.g. simple shaking), it may turn into a lyophobic colloid (with lower viscosity) – Thixotropy (gel-sol-gel transformation)  Gelling agents Semi-synthetic materials – Methylcellulose (MC) – Carboxymethylcellulose (CMC) – Hydroxyethylcellulose (HEC) – Hydroxypropylcellulose (HPC) – Hydroxypropyl methylcellulose (HPMC) Higher clarity of gel than MC  Gelling agents Natural gums – Acacia – Tragacanth (2 –5 %) Mixture of water-insoluble and water-soluble polysaccharides Negatively charged in aqueous solution – Xanthan – Alginate (1.5 –10 %) Clays – Bentonite – Aluminium magnesium silicate Synthetic materials – Carbomer (carboxyvinyl polymer)  Gelling temperature (Tg) Some polymer solutions turn into a gel at a given temperature, upon heating or cooling Poly vinyl alcohol solution turns into gels upon cooling – Tg ≠ mp point of gelling agent – Tg is usually quite broad (a range of temperature) – Higher concentration, ↑ Tg – ↑ Tg suggests that a higher energy is required to break the structure of the gel network  Gelling temperature (Tg) Concentrated poloxamer solutions turn into gel upon heating – Poloxamers form micelles at high concentrations (above CMC) – The polymer chains are better hydrated at low temperature – Increasing temperature will reduce the solubility of poloxamers – Increasing temperature will result in more micelles being formed, which can compact together to form gels Mechanisms of Carbomer uncoiling Carbomer (Polyacrylic acid) – contains 56 to 68% w/w carboxylic acid groups (-COOH) Convert the acidic molecule to a salt, e.g. – addition of NaOH or KOH for aqueous or polar solvent systems – addition of triethanolamine or diethanolamine for less polar or non-polar solvent systems – The –COOH groups are converted to –COO-Na+ (Charged) Viscosity of the resultant gel depends on the extent of polymer opening R-COOH and R-COO-Na-, which is more hydrophilic? Dry state, or low pH: COOH Randomly coiled polymer Wet state, high pH: Partially uncoiled polymer COO– upon hydration To maximise rigidity, the polymer must be fully uncoiled  Boots Mouth Ulcer Gel Active ingredients – Lidocaine base: 0.6 % w/w – Cetylpyridinium chloride: 0.02 % w/w Excipients of known effect – Ethanol (alcohol 96%): 35.00 % v/w – Sucrose (refined sugar): 5 % w/w Indications: pain caused by minor recurrent aphthous mouth ulcers Application: topical application to the mouth and gums List of excipients – Refined sugar – Cetomacrogol 1000 – Hypromellose – Ethanol 96% – Eucalyptol – Levomenthol synthetic or natural – Star anise oil – Purified water  Recommended reading Michael E Aulton and David Taylor (Ed). Aulton’s Pharmaceutics – the Design and manufacture of medicines, 4th edition and 5th edition Thank you!